1. Field of the Invention
The present invention relates to a composition for alleviating nephrotoxicity caused by an immunosuppressive drug, including metformin, and a composition for preventing or treating an immune disease, including the same, and more particularly, to a composition for reducing nephrotoxicity caused by an immunosuppressive drug, including metformin as an active ingredient, a pharmaceutical composition for preventing or treating an immune disease, including metformin and an immunosuppressive drug such as a calcineurin inhibitor as active ingredients, and a pharmaceutically combined preparation for preventing or treating an immune disease, including metformin and an immunosuppressive drug such as a calcineurin inhibitor as constituent elements, wherein the metformin and the calcineurin inhibitor are administered simultaneously, separately, or in a predetermined order.
2. Discussion of Related Art
Immunosuppressive drugs are drugs that block or reduce a humoral immune response in which antibodies are generated against antigens or cellular immune response, and thus have been generally used to treat immune rejection caused after organ transplantation, or graft-versus-host diseases after bone marrow transplantation.
In addition, the immunosuppressive drugs are of importance for use to treat autoimmune diseases such as lupus, rheumatoid arthritis, and the like, hypersensitive immune responses such as allergy, atopy, and the like, and inflammatory diseases over a long period of time.
Immunosuppressive drugs currently used in the art are divided into corticosteroids, antimetabolites, calcineurin inhibitors, mammalian targets of rapamycin inhibitors, antibodies, and the like, depending on their mechanisms of action. These drugs have an immunosuppressive effect by blocking the proliferation or activation of T cells in the immune system at different stages (Dalal, P. et al. Int. J. Nephrol. Renovasc. Dis. 3:107-115 (2010)). T cells which are a main target of the immunosuppressive drugs differentiate into two categories: type 1 T helper cells (Th1) which are generated in the human thymus to participate generally in cell-mediated immunity, and type 2 T helper cells (Th2) which participate in humoral immunity. Both of the T cell groups are known to keep each other in check, and atypical responses such as autoimmune response or hypersensitive response occur when the balance is broken in the groups.
In addition, new types of T cells such as immunoregulatory T cells (Tregs) or Th17 which can regulate immune responses are known in the art. Treg may adjust Th1 cell activities, and serves to suppress the function of abnormally activated immune cells and control an inflammatory response. On the other hand, the Th17 cells secrete IL-17, and serves to maximize signals for inflammatory responses so as to accelerate the progression of diseases. In recent years, as these Treg or Th17 cells have emerged as novel targets of therapeutic agents for treating an immune disease, much research on immunoregulatory therapeutic agents has been conducted (Wood, K. J. et al., Nat. Rev. Immunol. 12(6):417-430, 2012; Miossec, P. et al., Nat. Rev. Drug Discov. 11(10):763-776, 2012; Noack, M. et al., Autoimmun. Rev. 13(6):668-677, 2014).
In general, conventional immunosuppressive drugs that suppress T cells in a non-specific manner have a drawback in that it is difficult to last a therapeutic effect for a long period of time since they are accompanied by side effects such as cytotoxicity, infections caused by compromised immunity, diabetes, tremor, headache, diarrhea, hypertension, nausea, renal dysfunction, etc. Therefore, there have been attempts conducted to develop methods of co-administering or replacing immunosuppressive drugs having different mechanisms of action especially in the field of organ transplantation so as to reduce serious side effects and enhance an immunosuppressive therapeutic effect. However, there are no optimized combinations or therapies for co-administration of the immunosuppressive drugs.
Therefore, it is urgent to develop a novel immunosuppressive or immunomodulatory therapy capable of reducing the side effect of the conventional immunosuppressive drugs and improving the therapeutic effects and to screen novel immunosuppressive drug candidates which are safer and have few side effects.